This invention relates to the therapy of patients afflicted with chronic myelogenous leukemia (CML).
Chronic myelogenous leukemia (CML) is a chronic form of leukemia originating in a primitive myeloid stem cell in which the leukemic cells retain the capacity for differentiation and are able to perform the essential functions of normal hematopoietic cells that they replace in the marrow. The leukemic cells have a pronounced tendency to undergo further malignant transformation with loss of ability to differentiate in later stages of the disease. Although commonly included among other myeloproliferative disorders, CML is a distinct entity that is easily recognized because the leukemic cells have a distinctive cytogenetic abnormality, the Philadelphia (Ph.sup.1) chromosome (also designated Ph.sup.+).
The etiology is unknown. The majority of patients with CML have no history of excessive exposure to ionizing radiation or chemical leukemogens, but the incidence increases greatly with exposure to high doses of radiation.
The incidence of CML in the United States and most Western countries is about 1.5 per 100,000 population per year and accounts for about 15 percent of all cases of leukemia.
Chronic myelogenous leukemia is a uniclonal neoplastic proliferation of hematopoietic stem cells. In about 90 percent of cases the leukemic cells have the unique Philadelphia (Ph.sup.1) chromosome. The Ph.sup.1 anomaly results from a reciprocal translocation of a portion of the long arm of chromosome 22 to another chromosome, usually the long arm of chromosome 9, although sometimes to another chromosome. Both deletion of the long arm of number 22 and translocation to another chromosome must be demonstrated by appropriate banding studies in order to confirm Ph.sup.1 positivity.
The leukemic cells in chronic or benign phase CML have a striking propensity for further malignant transformation. After a variable duration of the chronic phase, averaging about three years, the disease enters an accelerated or, eventually, a blastic phase. Such malignant progression occurs in about 80 percent of patients and probably would eventually occur in all of them if they did not die of other complications of the disease or of unrelated causes. The rapidity with which the transition occurs depends on the degree of further transformation and on the comparative proliferative properties of the chronic and acute phase stem cells. In the accelerated phase the cells retain their capacity for partial differentiation, whereas in the blastic phase they are arrested at the blastic level of differentiation. The direction of differentiation in the accelerated phase is variable, as it is in the chronic phase. Transitional forms may occur between the chronic, accelerated, and blastic phases.
The most consistent laboratory abnormality at diagnosis of CML is leukocytosis. The white blood cell count (WBC) may range from a minimal elevation to over a million leukocytes per cubic millimeter. Increased numbers of eosinophils and/or basophils are often present, and sometimes monocytosis is seen. Increased megakaryocytes are often found in the marrow. The myeloid:erythroid ratio in the marrow is usually greatly elevated. The percentage of blasts in the marrow and blood is usually less than 3 percent in the chronic phase at diagnosis and less than 1 percent after the WBC has been reduced by treatment; a persistant elevation of greater than 10 percent usually indicates impending transformation. About half of patients present with some degree of thrombocytosis at diagnosis; thrombocytopenia is much less frequent. Extreme degrees of thrombocytopenia or thrombocytosis may develop as the disease progresses. In some patients, cyclic fluctuations of the leukocytes and platelets have been observed that are unrelated to treatment.
Transition from the chronic phase to the accelerated or blastic phase may occur gradually over a year or longer or abruptly ("blast crisis"). There are no standardized criteria for distinguishing between the accelerated and blastic phases, but most authorities use a persistant elevation of greater than 20 or 30 percent blasts in the blood and/or marrow or of blasts plus promyelocytes of 30 percent in blood or 50 percent in marrow to define the blastic phase.
Asymptomatic patients in the chronic phase in whom the WBC is below 50,000 per cubic millimeter can be observed without treatment until the disease progresses and symptoms develop. When clinical manifestations appear they can usually be controlled with cytotoxic drugs such as busulfan, or by splenic irradiation or splenectomy but unlike in acute leukemia, true remissions are very rare and the marrow remains largely populated with leukemic cells containing the Ph.sup.1 marker. Allogenic transplants have been employed successfully when compatible marrow has been available.
When CML enters an accelerated phase it becomes increasingly refractory to therapy that was previously effective. Increasing doses of busulfan or hydroxyurea are required to control the WBC and spleen size and, in some cases, progressive thrombocytosis. In some cases, severe anemia and/or thrombocytopenia develop, either because of the disease or as a result of drug toxicity.
Alpha interferon has been employed in clinical trials in an effort to treat GML (M. Talpaz et al., "Blood" 62:689-692 [1983]), and has received approval from the Food and Drug Administration for the treatment of hairy cell leukemia.
Gamma interferon, a structurally distinct molecule known to have a receptor site distinct from that of alpha interferon (M. Aguet et al., "Virology" 117:541 [1982]), has been proposed for use in treating malignancies. For example, see R. Silver et al., "The American Journal of Medicine" 80:1137 (June, 1986). A preliminary report of the results described herein was published by R. Kurzrock et al., "Blood" 66 (Sup. 1) 291a (Nov. 1985).
Gamma interferon is known to exert effects on leukemic cell growth and differentiation in in vitro cell culture (T. Hosoi et al., "Exp. Hematol." 13:597 [1985]; W. Rigby et al., "Blood" 65:858 [April 1985]; and S. Buessow et al., "J. Biol. Res. Mod." 3:653 [1984]).
Accordingly, methods are needed for the treatment and control of CML which are ore effective and which are not characterized by the severe side effects prevalent with conventional therapies for this disease.